JPH0720918B2 - Peptide compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Object] The present invention relates to a novel peptide compound having a renin-inhibitory action and good water solubility, oral absorbability and / or intestinal absorbability, and a pharmacologically acceptable salt thereof. is there.

As peptide derivatives having a renin-inhibiting action, tetrapeptides, tripeptide derivatives and the like have hitherto been known (JP-A-52-151166, etc.).

The inventors of the present application, for the synthesis of peptide derivatives and their renin inhibitory activity, as a result of extensive studies over many years, as a result, peptide compounds having a novel structure not known in the art have excellent renin inhibitory activity, It was found that the compound has good water solubility, oral absorbability and / or intestinal absorbability and can be an important intermediate for synthesizing the derivative,
The present invention has been completed.

〔Constitution〕

The peptide compound according to the present invention is a compound having the formula (I).

In the above formula, R ¹ is a group of the formula —B—R ⁷ (in the formula, B represents a linear or branched lower alkylene group, and R ⁷ is an aryl group, a heteroaryl group or a heterocyclylcarbonyl group. Or a group of the formula —E—R ⁸ (wherein E represents a lower alkylene group which may be interrupted by one oxygen atom, R ⁸ represents a lower alkoxy group, an aryloxy group, an arylthio group,
An aralkyloxy group or a heterocyclyl group is shown. And R ² represents an aryl group or a heteroaryl group, R represents a hydrogen atom or a lower alkyl group, and R ³ represents a hydrogen atom or an optionally substituted C ₁ -C ₁₀ alkyl group. (The substituent may be one or two, and they are a halogen atom, a trifluoromethyl group, a trichloromethyl group, a hydroxyl group, a lower alkoxy group, an aryloxy group, an aralkyloxy group, a lower aliphatic acyloxy group, a mercapto group,
Lower alkylthio group optionally substituted with lower aliphatic acylamino, arylthio group, aralkylthio group, lower alkylsulfinyl group, arylsulfinyl group, lower alkylsulfonyl group, arylsulfonyl group, amino group, mono- or di- Lower alkylamino group, arylamino group, lower aliphatic acylamino group, arylacylamino group, lower alkoxycarbonylamino group, aralkyloxycarbonylamino group, carboxy group, lower alkoxycarbonyl group, aryloxycarbonyl group,
Aralkyloxycarbonyl group, carbamoyl group, mono- or di - lower alkylcarbamoyl group, a ureido group, thioureido group, Kuanijiru group, C ₃ -C ₇ cycloalkyl group, C ₅ -C ₈ cycloalkenyl group, an aryl group or a heteroaryl group Indicates. ), C ₃ -C ₅ alkenyl group, C ₃ -
C ₅ alkynyl group, C ₃ -C ₇ cycloalkyl group, C ₅ -C ₈ cycloalkenyl group, an aryl group or a heteroaryl group, R ⁴ is an isopropyl group, a cycloalkyl group or a phenyl group of C ₃ -C ₇ R ⁵ represents a linear or branched C ₁ -C ₅ alkyl group, R ⁶ represents a substituted C ₁ -which may be interrupted by a nitrogen atom.
C ₁₀ alkyl group [wherein the substituents may be 1, 2 or 3 and these are amino group, 6-membered cyclic heterocyclyl lower alkylamino group, hydroxy lower alkylamino group, guanidyl group, substituted phenyl Group (substituent on the ring is amino in addition to amino lower alkyl group or hydroxyl group,
A lower alkoxy group having mono-lower alkylamino, di-lower alkylamino, heterocyclyl or heterocyclyl lower alkylamino as a substituent is shown. ), A sulfo group, a hydroxyl group, a carboxy group, a lower alkoxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylcarbamoyl group, or a pyridinyl group. ] Is shown. However, the C ₁ -C ₁₀ alkyl group of R ⁶ is an amino group, a 6-membered cyclic heterocyclyl lower alkylamino group, a hydroxy lower alkylamino group, a guanidyl group, a substituted phenyl group or a substituted group of a sulfo group. Be sure to have one or more selected substitutions.

The groups defined in compound (I) have the following meanings.

The linear or branched lower alkylene group for B represents a C ₁ -C ₄ alkylene group, and examples thereof include methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, n-propylmethylene and 2-ethylethylene. , 3-
Examples thereof include methyltrimethylene and 2-methyltrimethylene.

An aryl group such as R ² , R ³ , R ⁷ and R ⁸ or an aralkylthio group,
The aryl moiety such as aryloxy group or arylthio group represents optionally substituted phenyl, indenyl or naphthyl. As the substituent, 1 to 3 may be present, and examples thereof include a lower alkyl group, a halogen atom such as fluorine, chlorine, bromine and iodine (hereinafter, the halogen atom has the same meaning). A lower alkoxy group, a lower alkoxycarbonyl group, a trifluoromethyl group, an amino group, a cyano group or a nitro group is shown. The lower alkyl moiety such as a lower alkyl group, a lower alkylamino group or a lower alkoxy group may be, for example, methyl,
Examples thereof include ethyl, n-propyl, isopropyl, n-butyl, isobutyl, S-butyl or t-butyl (hereinafter, lower alkyl group and the like have the same meaning).

The heteroaryl group such as R ² , R ³ and R ⁷ may be condensed with a phenyl ring and represents a 5- to 6-membered cyclic aromatic group containing an oxygen, sulfur or / and nitrogen atom, for example, furyl, Thienyl,
Oxazolyl, thiazolyl, pyridyl, benzofuryl,
Benzothiophenyl, indolyl, benzthiazolyl,
Examples thereof include benzimidazolyl, quinolyl and isoquinolyl, and the ring may have a substituent, and examples of the substituent include a lower alkyl group, a halogen atom and a lower alkoxy group.

The heterocyclyl group of R ⁶ , R ⁷ and R ⁸ or the heterocyclyl moiety of the heterocyclylcarbonyl group has 1 or 2 nitrogen atoms.
And a 5- or 6-membered cyclic group which may contain oxygen or sulfur atom, and examples thereof include piperidyl, pyrrolidyl, morpholinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl or piperazinyl, and a substituent on the ring. The substituent which may be present is, for example, lower alkyl, hydroxy lower alkyl, lower alkoxy, optionally substituted phenyl (the substituents are the same as the above-mentioned substituents of the aryl group), hetero. Examples thereof include aryl, aralkylcarboxy, lower aliphatic acyl, heteroarylacyl, lower alkoxycarbonyl, pyridyl or cinnamoyl (the substituent on the phenyl ring is the same as the substituent on the aryl group).

One good lower alkylene group which may be interrupted by oxygen atoms E is an alkylene group of C ₁ -C _4, for example, C ₁ -C ₄ alkylene or wherein CH ₂ -O-CH ₂ in the B -,-
_{CH 2 CH 2 -O-CH 2} -, CH 2 -O-CH 2 CH 2 - or -CH ₂ CH
₂ -O-CH ₂ CH ₂ - can be mentioned a group having a.

Aralkyl moiety of R ^3, an aralkyl group or an aralkyloxy group contained in R ⁸ or the like, aralkyloxycarbonyl groups, such as an aralkyloxycarbonyl amino group or aralkylthio group, a lower alkyl group substituted with an aryl group, for example, Examples thereof include a benzyl group, a phenethyl group, and a 4-phenylbutyl group.

Examples of the C ₁ -C ₁₀ alkyl group of R ³ include, in addition to the above C ₁ -C ₄ alkyl group, n-pentyl, 1-methylbutyl, isopentyl, 2-methylbutyl, s-pentyl, n-hexyl, Mention may be made of s-hexyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, n-heptyl, n-octyl, 1,5-dimethylhexyl, n-nonyl or n-decyl.

A lower aliphatic acyl group or the like which is a substituent of an acyl moiety such as a lower aliphatic acylamino group or a heterocyclyl group in R ^3, is a C ₁ -C ₄ acyl group, for example, formyl, acetyl, propionyl, butyryl or isobutyryl. Can be raised.

C ₃ -C ₇ cycloalkyl group in R ³ or R ⁴ is, for example, cyclopropyl, cyclobutyl, cyclopentyl,
A cyclohexyl or cycloputyl group is shown.

C ₅ -C ₈ cycloalkenyl group for R ³ includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl.

Examples of the C ₃ -C ₅ alkenyl group for R ³ include allyl, methallyl, 2-butenyl, 3-butenyl or 2-pentenyl.

Examples of the C ₃ -C ₅ alkynyl group for R ³ include propargyl, 2-butynyl, 3-butynyl and 2-pentynyl.

Examples of the C ₁ -C ₅ alkyl of R ⁵ include n-pentyl and isopentyl in addition to the above C ₁ -C ₄ alkyl group.

Substituted C ₁ -C optionally interrupted by the nitrogen atom of R ⁶
_The portion excluding the substituent of the alkyl group of ₁₀ is, for example,
In addition to the same groups as the C ₁ -C ₁₀ alkyl group in R ³ etc.,
Formula CH _{2 2} NH-CH ₂ CH ₃ , _{- (CH 2) 2 -NH- (} CH 2) 2 NH-CH 2 CH 3, - (CH 2) 3 -NHCH 2 2 CH 3 or A group having

The 6-membered cyclic heterocyclyl moiety of the 6-membered cyclic heterocyclyl lower alkylamino group which is a substituent of the C ₁ -C ₁₀ alkyl group of R ⁶ is preferably 4-methylpiperazino, 4-phenylpiperazino or morpholino. is there.

Further, in the compound (I), suitable groups for R ¹ , R ² , R ³ , R ⁵ and R ⁶ are, for example, as follows.

R ¹ : CH ₃ OCH ₂ CH ₂ −, CH ₃ CH ₂ OCH ₂ CH ₂ −, CH ₃ OCH _{2 2} OCH
_{2 2} , CH ₃ CH ₂ -OCH _{2 2} O (CH _{2 2} , R ² : ^{_{R: H, CH 3 R 3}} : H, -CH 3, -CH 2 CH 3, -n-C 3 H 7, -i-C 3 H 7, -n-C 4 H 9, -i-C 4 _{H 9, -s-C 4 H} 9, -n-C 5 H 11, -i-C 5 H 11, -n-C 6 H 13, -n-C 7 H 15, -n-C 8 -H _{17, -n-C 9 C 19} , -n-C 10 H 21, -CH 2 F, -CH 2 Cl, -CH 2 CHCl 2, -CH 2 CCl 3, _{-CH 2 OCH 3, -CH 2 OCH} 2 CH 3, -CH 2 O-t-C 4 H 9, -CH 2 CH 2 OCH 3, -CH 2 CH 2 OCH 2 CH 3, _{-CH 2 SH, -CH 2 CH 2} SH, -CH 2 -S-CH 2 NHCOCH 3, -CH 2 -CH 2 -S-CH 3, -CH 2 -CH 2 -S-CH 2 CH 3, CH _{2 3} S-CH ₃ , CH _{2 4} S-C
H ₃ , _{-CH 2 CO 2 H, -CH 2} CH 2 CO 2 H, -CH 2 CO 2 CH 3, -CH 2 CO 2 - t C 4 H 9, -CH 2 CH 2 CO 2 - t C 4 H 9, _{^{R 5: -n-C 3 H}} 7, -i-C 3 H 7, -n-C 4 H 9, -i-C 4 H 9, -s-C 4 H 9, -n-C 5 H 11 , -I-C ₅ H ₁₁ R ⁶ : H ₂ NCH ₂ CH _2- , H ₂ NCH ₂ ) _3- , H ₂ NCH _{2 4} H ₂ NCH _{2 5} , H ₂ NCH _{2 6} ,, H ₂ NCH _{2 8} H ₂ NCH _{2 9} , When compound (I) has an optical isomer based on an asymmetric carbon, it includes an optically active substance and a racemate,
Preferably a formula Part is S-coordinate It is a compound in which the moiety is in the S configuration.

The compound having the above general formula (I) of the present invention can be made into a pharmaceutically acceptable salt. Examples of such salts include mineral salts such as hydrochlorides, sulfates, phosphates, oxalates, maleates, succinates, organic salts such as citrates, methanesulfonate, Acid addition salts such as sulfonates such as benzene sulfonate and P-toluene sulfonate, alkali metal salts or alkaline earth metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt, dicyclohexylamine salt An organic base salt such as

In the compound (I), preferably, (1) R ¹ is a group having a group of the formula —B—R ⁷ (wherein B is C ₁ —
C _{3 represents} an alkylene group, and R ⁷ represents an aryl group, a heteroaryl group or a heterocyclylcarbonyl group. ) Is a compound, (2) a compound in which R ² is an aryl group, (3) a compound in which R is a hydrogen atom or a methyl group, (4) phenyl, heteroaryl or R ³ which may be composed of a hydroxyl group. optionally substituted carbamoyl lower alkyl group, an alkenyl group or C C ₃ -C _{5 3} -C ₅
Which is an alkynyl group, (5) a compound in which R ⁴ is an isopropyl group, a cyclohexyl group or a phenyl group, (6) a compound in which R ⁵ is an isopropyl group, an isobutyl group or an S-butyl group, (7) R ⁶ Is optionally substituted with a nitrogen atom
C ₁ -C ₁₀ alkyl group (the number of the substituents may be 1 to 3, and these may be an amino group, a hydroxy lower alkylamino group, a guanidyl group, a hydroxyl group, a carboxy group, a lower alkoxycarbonyl group, a carbamoyl group. Group, a mono- or di-lower alkyl-substituted carbamoyl group or an amino-lower alkyl-substituted phenyl group, provided that the substitution selected from the group consisting of amino group, hydroxy-lower alkylamino group, guanidyl group and substituted phenyl group (8) R ¹ is a group having the formula —B—R ⁷ (wherein B is C ₁ -C _3).
R ⁷ represents an aryl group, a heteroaryl group or a heterocyclylcarbonyl group. ), R ² is an aryl group, R is a hydrogen atom or a methyl group, and R ³ is phenyl optionally substituted with a hydroxyl group,
Heteroaryl or optionally substituted lower alkyl group carbamoyl, C ₃ -C ₅ alkenyl group or a C ₃ -
C _{5 is} an alkynyl group, R ⁴ is an isopropyl group, a cyclohexyl group or a phenyl group, R ⁵ is an isopropyl group, an isobutyl group or an S-butyl group, and R ⁶ may be interrupted by a nitrogen atom. Substituted C ₁ -C ₁₀ alkyl group (the number of the substituents may be 1 to 3 and they may be an amino group, a hydroxy lower alkylamino group, a guanidyl group, a hydroxyl group, a carboxy group, a lower alkoxycarbonyl group. Group, carbamoyl group, mono- or di-lower alkyl-substituted carbamoyl group, or phenyl group substituted with amino-lower alkyl, provided that it is selected from the group consisting of amino group, hydroxy lower alkylamino group, guanidyl group, and substituted phenyl group. (9) R ¹ is a group having the formula —B—R ⁷ (wherein B is a C ₁ -C _{3 group} ). An alkylene group, R ⁷ represents a phenyl group, a naphthyl group, a pyridyl group or a 5- to 6-membered heterocyclylcarbonyl group), (10) a compound in which R ² is a naphthyl group or a phenyl group, (11) ) A compound in which R ³ is a lower alkyl group optionally substituted with a 5-membered heteroaryl, (12) R ⁶ is optionally substituted with a nitrogen atom
A C ₁ -C ₁₀ alkyl group (having 2 to 3 substituents,
An amino group, a hydroxy lower alkylamino group, a guanidyl group, a hydroxyl group, a carboxy group, a lower alkoxycarbonyl group or a carbamoyl group is shown. However, it always has at least one substituent selected from the group of substituents of amino group, hydroxy lower alkylamino group, guanidyl group and substituted phenyl group. (13) A compound in which R ³ is a lower alkyl group substituted with thiazolyl. Furthermore, in the compound (I), preferably,
The compounds exemplified in Tables 1-4 below can be given.

Further, in Table 1 above, among the compounds of the compound numbers 1, 3, 9, and 11, the corresponding compounds in which R is a methyl group can be specifically mentioned as preferable examples.

The compound of the present invention having the general formula (I) can be easily produced according to the following method.

Method A Method B C method In the above formula, R ¹ , R ² , R, R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as described above, and ▲ R ³ _a ▼ represents an amino group or a guanidyl group contained in R ^3. And a carboxy group are protected, and have the same meaning as R ^3, and ▲ R ⁶ _a ▼ is an amino group contained in R ⁶ ,
A guanidyl group, a carboxy group and a sulfo group are protected, and it has the same meaning as R ⁶ and R ⁹ represents a lower alkyl group or an aralkyl group.

The protecting group for ▲ R ³ _a ▼ and ▲ R ⁶ _a ▼ is not particularly limited as long as it is a protecting group used in the field of amino acid chemistry, and for example, as the protecting group for amino group, benzyloxycarbonyl, p- Examples thereof include an aralkyloxycarbonyl group such as methoxybenzyloxycarbonyl, a carbonate residue such as t-butyloxycarbonyl group or 9-fluorenylmethyloxycarbonyl group, and examples of the protecting group for the carboxy group or the sulfo group include , A lower alkyl group such as methyl, ethyl, n-propyl and t-butyl, or an aralkyl group such as a benzyl group. Examples of the guanidyl group-protecting group include
A sulfonyl group such as p-toluenesulfonyl group may be mentioned.

Method A is a method for producing compound (I).

The first step of this method is a step of producing compound (Ia) using compound (II) or its reactive derivative and compound (III), which is a conventional method in peptide synthesis, such as azide method, active ester method, mixing method. It is carried out by the acid anhydride method or the carbodiimide method.

In the above peptide synthesis, the azide method is a method in which an amino acid or an ester thereof is treated with hydrazine in an inert solvent (for example, dimethylformamide),
It is carried out by reacting the amino acid hydrazide produced by reacting at around room temperature with a nitrite compound to convert it into an azide compound, and then treating with an amine compound.

Examples of the nitrite compound used include alkali metal nitrites such as sodium nitrite or alkyl nitrites such as isoamyl nitrite.

The reaction is preferably carried out in an inert solvent, and examples of the solvent used include amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, and pyrrolidones such as N-methylpyrrolidone. Can be raised. Also, the two steps of this method are usually carried out in one reaction solution, and the reaction temperature is
The former is -50 ° C to 0 ° C, the latter is -10 ° C to 10 ° C, and the time required for the reaction is 5 minutes to 1 hour in the former and 10 hours to 5 days in the latter.

The active ester method is carried out by reacting an amino acid with an active esterifying agent to produce an active ester and then reacting it with an amine compound.

Both reactions are preferably carried out in an inert solvent, and examples of the solvent used include halogenated hydrocarbons such as methylene chloride and chloroform, ethers, ethers such as tetrahydrofuran, dimethylformamide and dimethyl. Amides such as acetamide may be mentioned.

Examples of the active esterifying agent used include N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and N-hydroxy-5-norbornene-2,3-dicarboximide. The active esterification reaction can be carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide or carbonyldiimidazole.

The reaction temperature is −10 to 10 ° C. for the active esterification reaction, and is around room temperature for the reaction between the active ester compound and the amine, and the time required for the reaction is 30 minutes to 10 ° C. for both reactions.
It's time.

The mixed acid anhydride method is carried out by producing a mixed acid anhydride of amino acids and then reacting it with an amine.

The reaction to produce the mixed acid anhydride is carried out in an inert solvent (for example,
In the above amides and ethers), ethyl chlorocarbonate,
This is achieved by reacting the amino acid with a lower carbonic acid carbonate such as isobutyl chlorocarbonate or a dilower alkylcyanophosphoric acid such as diethyl cyanophosphoric acid.

The reaction is preferably carried out in the presence of an organic amine such as triethylamine or N-methylmorpholine, the reaction temperature is -10 ° C to 10 ° C, and the reaction time is 30 minutes to 5 hours. .

The reaction of the mixed acid anhydride and the amine is preferably carried out in an inert solvent (for example, the above amides and ethers) in the presence of the above organic amine, and the reaction temperature is 0 ° C to room temperature, The time required for the reaction is 1 hour to 24 hours.

The condensation method is carried out by directly reacting an amino acid with an amine in the presence of a condensing agent such as dicyclohexylcarbodiimide or carbonyldiimidazole. This reaction is carried out in the same manner as the above-mentioned reaction for producing an active ester.

In the second step, the protecting groups for the amino group, guanidyl group, carboxy group and sulfo group contained in ▲ R ³ _a ▼ and / or ▲ R ⁶ _a ▼ in compound (Ia) are removed to give compound (I)
Is a process of manufacturing.

The removal reaction of the protecting group differs depending on the type of the protecting group,
It is performed according to the usual method.

For example, when the amino-protecting group is a t-butyloxycarbonyl group and when the carboxy or sulfo-protecting group is a t-butyl group, it is in an inert solvent (for example, dioxane, methanol, dimethylformamide). Etc.) and the corresponding compound with an acid (for example, hydrochloric acid, trifluoroacetic acid, trifluoroborone etherate, etc.) at 0 ° C. to
It is carried out by treating at 30 ° C. for 20 minutes to 1 hour.

When the amino-protecting group is an aralkyloxycarbonyl group or a carbonate residue and the carboxy- or sulfo-protecting group is an aralkyl group, in an inert solvent (for example, methanol, ethanol, tetrahydrofuran, etc.), The corresponding compound in the presence of a catalytic reduction catalyst (eg palladium-carbon, palladium black, etc.) at atmospheric pressure to 10
It is carried out by reacting with hydrogen at atmospheric pressure near room temperature for 2 to 8 hours.

When the protective group for the carboxy group or the sulfo group is a lower alkyl group, it is mixed with an alkali (eg, sodium hydroxide, potassium hydroxide, etc.) in an inert solvent (eg, sodium hydroxide, potassium hydroxide, etc.) at 0 ° C. to It is carried out by reacting at 30 ° C. for 2 to 5 hours.

When the protecting group for the guanidyl group is a sulfonyl group,
In the presence of a cation trapping agent (eg, anisole, thioanisole, etc.), the corresponding compound is treated with an acid (eg, hydrofluoric acid, trifluoromethanesulfonic acid, etc.) at 0 ° C to 40 ° C.
At 15 minutes to 1 hour.

Further, if desired, the amino group contained in R ³ and R ⁶ can be converted into a guanidino group.

Conversion of an amino group to a guanidino group can be carried out by reacting 1-guanyl-3,5-dimethylpyrazole nitrate in the presence of a base such as triethylamine in an inert solvent (eg, dimethylformamide) at 10 ° C to 25 ° C for 1 day to 7 days. Achieved by reacting for a day [eg RAB Bannard et. Al, Ca
nJChem, 36 , 1541 (1958)].

The method B is a method for separately producing the compound (Ia), and the third step of the method is the method A using the compound (IV) and the compound (V).
It is performed in the same manner as the process.

Compound (IV) is produced by a malonic acid synthesis method using a halide corresponding to malonic acid ester (Orga
nic Synthesis.Coll.voI.3,705).

Method C is a method for separately producing compound (Ia).

The fourth step is a step of producing a compound having the general formula (VII), and is achieved by reacting compound (IV) with compound (VI) and hydrolyzing the obtained compound. The reaction of compound (IV) with compound (VI) is carried out in the same manner as in the above-mentioned Method A 1st step, and the hydrolysis reaction is a deprotection reaction in the case where the carboxy-protecting group in Method A is a lower alkyl group. The same is done as.

The fifth step is a step of producing a compound having the general formula (Ia), which comprises converting the compound (VII) into a compound of the general formula (VII) in an inert solvent.
This is achieved by reacting with the amine compound having I), and this step is performed in the same manner as the first step of Method A.

After completion of the reaction in each of the above steps, each target compound can be collected from the reaction mixture according to a conventional method. For example, the desired product can be obtained by appropriately neutralizing the reaction mixture, or, if an insoluble substance is present, removing it by filtration and then distilling off the solvent. Further, if desired, it can be purified by a conventional method, for example, recrystallization, reprecipitation, column chromatography and the like.

〔effect〕

The results of the inhibitory action test of the peptides having the general formula (I) of the present invention on human renin are shown below. In addition, the test method is the method of Kokufu et al. [Hypertension, 5 , 191-19: 00
7 (1983)], the peptide of the present invention was premixed with a sheep renin substrate, and then human renin was added.

The object compound (I) of the present invention exhibited an excellent inhibitory action on human renin as shown in the above test examples.
Further, the compound (I) exhibited excellent effects by intestinal administration using marmosets and had good solubility in water. Therefore, it is useful as a diagnostic and therapeutic agent for hypertension based on the renin-angiotensin system, especially for oral use. Examples of the dosage form include tablets, capsules,
Not only oral administration by granules, powders, syrups, etc., but also parenteral administration by injections, suppositories, etc. can be mentioned. The usage amount varies depending on the purpose of use, symptoms, age, etc., but is, for example, about 0.01 mg to 100 mg / kg body weight per day, and it can be administered once or in several divided doses.

Next, the present invention will be described more specifically with reference to Examples and Reference Examples. In the following examples, the statyl group is
(3S, 4S) -4-amino-3-hydroxy-6-methylheptanoyl group, and statin is (3S, 4S) -4-
Amino-3-hydroxy-6-methylheptanoic acid.

Example 1. N ^α- [bis (1-naphthylmethyl) acetyl] -L-
Histidyl-statyl-L-leucyl-ε-L-lydinol a) N-benzyloxycarbonyl-L-leucyl-N
^α- t-butoxycarbonyl-ε-L-lydinol N-benzyloxycarbonyl-L-leucine-N-hydroxysuccinimide ester 1.81 g (5 mmol)
And N ^α- t-butoxycarbonyl-L-ridinol 1.16
Dissolve g (5 mmol) in 25 ml of methylene chloride and mix at room temperature for 1
It was stirred for a day. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed successively with 1N sulfuric acid, water, 5% aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the solid residue, and the solid residue was scraped off to obtain 2.13 g of the title compound as a colorless powder.

Melting point 119-123 ° C ▲ [α] ²² _D ▼ -22.0 ° (c = 0.5, methanol) Elemental analysis value Calculated C, 62.02; H, 8.64; N, 8.68 Found C, 62.21; H, 8.68; N, 8.68 b) N ^α- [bis (1-naphthylmethyl) acetyl]-
L-histidyl-statyl-L-leucyl-ε-L-lydinol N ^α- [bis (1-naphthylmethyl) acetyl] -L-
0.65 g (1 mmol) histidyl-statin hydrazide
Was dissolved in 6 ml of dimethylformamide, cooled to −60 ° C., 0.84 ml of 4N hydrochloric acid / dioxane solution and 0.2 ml of isoamyl nitrite were added, and the mixture was stirred at −20 ° C. for 10 minutes. The reaction solution was cooled again to -60 ° C, and N-methylmorpholine 0.34 was added.
(3.4 mmol) was added to neutralize. To this, 0.48 g (1 mmol) of N-benzyloxycarbonyl-L-leucyl-N ^α- t-butoxycarbonyl-L-lysinol
L-leucyl-N obtained by hydrogenolysis of the benzyloxycarbonyl group of 10% using 10% palladium-carbon as a catalyst.
5 ml of a solution of ^α- t-butoxycarbonyl-L-lydinol hydrochloride in dimethylformamide and N-methylmorpholine
0.11 g (1.1 mmol) was added, and the mixture was stirred at 4 ° C for 2 days.
A double amount of ethyl acetate was added to the reaction solution, washed with 1N sulfuric acid, 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue hula Tsu Shiyu column chromatography was purified (developing solvent methylene chloride / methanol ^{= 10/1), N α} - [bis (1-naphthylmethyl) acetyl] -L- Hisuchijiiru - Sutachiru -L- leucyl -N 0.40 g of ^α- t-butoxycarbonyl-L-lysinol was obtained as a pale yellow powder. 4N hydrochloric acid /
The mixture was treated with 10 ml of a dioxane solution at room temperature for 30 minutes, concentrated under reduced pressure and dried. Ethyl acetate was added to the solid residue and the mixture was collected and collected to obtain 0.38 g of the target compound as a pale orange powder.

Melting point 127-130 ° C ▲ [α] ²² _D ▼ -36.6 ° (c = 0.5, methanol) Elemental analysis value C ₅₀ H ₆₇ N ₇ O ₆・ 2HCl ・ 3H ₂ O Calculated value C, 60.71; H, 7.64; N, 9.91; Cl, 7.17 Found C, 60.83; H, 7.48; N, 9.65; Cl, 7.32 Example 2. N- [2 (RS)-(1-naphthyl) methyl-3- (3-
Pyridyl) propionyl] -3- (4-thiazolyl)-
DL-alanyl-statyl-L-leucyl-ε-lysine amide dihydrochloride a) N- [2 (RS)-(1-naphthyl) methyl-3-
(3-Pyridyl) propionyl] -3- (4-thiazolyl) -DL-alanine methyl ester 3- (4-thiazolyl) -DL-alanine methyl ester hydrochloride 1.3 g (5 mmol), 2- (1-naphthyl) 1.46 g (5 mmol) of methyl-3- (3-pyridyl) propionic acid was dissolved in 25 ml of dimethylformamide, and the mixture was cooled with ice.
0.82 g (5 mmol) of diethyl cyanophosphate and 1.66 g (16.5 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue is silica gel column chromatography (developing solvent:
It was purified with chloroform / methanol = 20/1). The target eluate was collected and concentrated under reduced pressure to obtain 1.58 g of the desired product.

Mp 133-135 ° C. Elemental analysis C ₂₆ H ₂₅ N ₃ O ₃ Calculated: C, 67.95; H, 5.48 ; N, 9.14; S, 6.98 Found: C, 67.86; H, 5.61 ; N, 8.95; S, 6.69 b) N- [2 (RS)-(1-naphthyl) methyl-3-
(3-Pyridyl) propionyl] -3- (4-thiazolyl) -DL-alanine hydrazide N- [2 (RS)-(1-naphthyl) methyl-3- (3-
Pyridyl) propionyl] -3- (4-thiazolyl)-
1.38 g (3 mmol) of DL-alanine methyl ester was dissolved in 15 ml of dimethylformamide, and 3.75 g (60 mmol) of 80% hydrazine hydrate was added under ice-cooling, followed by 4 at room temperature.
Stir for hours. After standing overnight, the mixture was concentrated under reduced pressure, water was added to the residue, and the precipitated crystals were collected and recrystallized from water to obtain 1.05 g of the desired product.

Mp 174-176 ° C. Elemental Analysis _{C 25 H 25 N 5 O 2} S · H 2 O Calculated: C, 62.87; H, 5.70 ; N, 14.66; S, 6.72 Found: C, 62.71; H, 5.43 ; N, 14.72; S, 6.62 C) N-t-Butoxycarbonyl-statyl-L-leucyl-N ^α -benzyloxycarbonyl-L-lysine amide N ^α -benzyloxycarbonyl-N ^ε- t-butoxycarbonyl-L-lysine Dissolve 6.0 g (15.8 mmol) in 50 ml of methylene chloride, and add 1.83 g (1
8.3 mmol), isobutyl chloroformate 2.5 g (18.
(3 mmol) was added dropwise under ice cooling and the mixture was stirred. After 30 minutes, 10 ml of a methanol solution saturated with ammonia was added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction mixture under reduced pressure,
% Sodium hydrogen carbonate solution was added, the mixture was filtered, and the crystals were washed with ether to give N ^α -benzyloxycarbonyl-N ^ε -as white crystals.
5.1 g of t-butoxycarbonyl-L-lysine amide was obtained. 2.8 g (10.0 mmol) of this amide without purification
20 ml of 4N hydrochloric acid / dioxane solution was added to the mixture, and the mixture was stirred at room temperature for 30 minutes to remove t-butoxycarbonyl group.
The reaction solution was concentrated under reduced pressure to dryness, 1.7 g (7.4 mmol) of Nt-butoxycarbonyl-L-leucyl was added to the residue, and further 40 ml of methylene chloride and 1.78 g of triethylamine (17.
(8 mmol) was added to make a suspension, 1.45 g (9.1 mmol) of diethyl cyanophosphate was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, 10% aqueous sodium hydrogen carbonate was added, the mixture was filtered, and the crystals were washed with ether to give Nt-butoxycarbonyl-L-leucyl-N ^α -benzyloxycarbonyl-L-lysine amide as white crystals. Obtained 3.5 g. 2.3 g (4.5 mmol) of this amide without purification
20 ml of 4N hydrochloric acid / dioxane solution was added to
The mixture was stirred for 1 minute to remove the t-butoxycarbonyl group. The reaction solution was concentrated to dryness under reduced pressure, and 1.24 g (4.5 mmol) of Nt-butoxycarbonyl-statin was added to the residue.
Furthermore, 30 ml of methylene chloride. And triethylamine 1.08
g (1.07 mmol) was added to make a suspension, 0.88 g (5.4 mmol) of diethyl cyanophosphate was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, 10% aqueous sodium hydrogen carbonate was added, the mixture was filtered, and the crystals were washed with ether to give Nt-butoxycarbonyl-statyl-L-leucyl-N ^α -benzyloxycarbonyl-L as white crystals. -1.90 g of lysine amide was obtained.

d) N- [2 (RS)-(1-naphthyl) methyl-3-
(3-Pyridyl) propionyl] -3- (4-thiazolyl) -DL-alanyl-statyl-L-leucyl-N ^α-
Benzyloxycarbonyl-L-lysine amide N- [2 (RS)-(1-naphthyl) methyl-3- (3-pyridyl) propionyl] -3 synthesized in Example 2b)
-(4-thiazolyl) -DL-alanine hydrazide 0.46 g
(1 mmol) was dissolved in 10 ml of dimethylformamide,
The mixture was cooled to -5 ° C, 0.85 ml of 4N hydrochloric acid / dioxane solution and 0.18 ml of isoamyl nitrite were added, and the mixture was stirred at the same temperature for 10 minutes. To this, 0.35 g (3.5 mmol) of N-methylmorpholine was added for neutralization. To this was added Nt-butoxycarbonyl-statyl-L-leucyl-N ^α -benzyloxycarbonyl-L-lysineamide synthesized in Example 2c).
0.63 g (1 mmol) of t-butoxycarbonyl group was added to 4
Statyl-L-leucyl-N ^α- t-butoxycarbonyl-L obtained by removal with normal hydrochloric acid / dioxane
5 ml of lysine amide hydrochloride in dimethylformamide
And 0.1 g (1 mmol) of N-methylmorpholine were added and 4
Stirred at 2 ° C for 2 days. A double amount of methyl acetate was added to the reaction solution, which was washed with 1N sulfuric acid, 5% aqueous sodium bicarbonate solution and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography (developing solvent: methylene chloride / methanol = 10/1) and N
-[2 (RS)-(1-Naphtyl) methyl-3- (3-pyridyl) propionyl] -3- (4-thiazolyl-DL-
0.53 g of alanyl-statyl-L-leucyl-N ^α -benzyloxycarbonyl-L-lysine amide was obtained.

Melting point 140-145 ° C Elemental analysis value: Calculated: C, 64.55; H, 7.05; N, 11.36; S, 3.25 Found: C, 64.55; H, 7.14; N, 11.36; S, 3.25 e) N- [2 (RS)-(1-naphthyl ) Methyl-3-
(3-Pyridyl) propionyl] -3- (4-thiazolyl) -DL-alanyl-statyl-L-leucyl-ε-L
-Lysine amide dihydrogen fluoride salt N- [2 (RS)-(1-naphthyl) methyl-3- (3-
Pyridyl) propionyl] -3- (4-thiazolyl)-
DL-alanyl-statyl-L-leucyl-N ^α -benzyloxycarbonyl-L-lysine amide 0.53 g is dissolved in 10 ml of hydrogen fluoride salt, a small amount of anisole is added as a cation trap agent, and the mixture is stirred under ice cooling for 30 minutes. did. This was concentrated under reduced pressure to dryness, diethyl ether was added to the obtained residue, and the residue was collected and taken as a white powder to give 0.5 g of the desired product.
Got

Melting point 150-155 ° C. Example 3. N- [2 (R) -benzyl-1,4-dioxo-4-morpholino] butyl-3- (4-thiazolyl-DL-alanine-statyl-L-leucyl-ε- L-lysine amide-2
Hydrofluoride a) N- [2 (R) -benzyl-1,4-dioxo-4-
Morpholino] butyl-3- (4-thiazolyl-DL-alanine methyl ester) 1.60 g (5.77 mmol) of the carboxylic acid synthesized in Reference Example 6
And DL-4-thiazolylalanine methyl ester-2
Hydrochloric acid salt 1.79 g (6.91 mmol) was dissolved in anhydrous tetrahydrofuran 50 ml, and under ice cooling under nitrogen atmosphere, diethyl cyanophosphate 1.05 ml (6.92 mmol) and triethylamine 2.66 ml (1.91 mmol) were added, and at the same temperature for 3 hours. It was stirred. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol = 20/1) to give the title compound as a colorless oily substance.
2.10 g (82%) was obtained.

Mass spectrum, m / e: 445 (M ⁺ ) b) N- [2 (R) -benzyl-1,4-dioxo-4-
Morpholino] butyl-3- (4-thiazolyl) -DL-alanine hydrazide 2.00 g (4.49 mmol) of the methyl ester synthesized in Example 3a) was dissolved in 15 ml of methanol to give hydrazine, 1
The hydrate (1.59 g, 31.4 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the obtained residue was washed with dimethyl ether and dried to give the title compound.
Obtained 1.70 g (85%).

Mass spectrum, m / e: 445 (M ⁺ ) c) N- [2 (R) -benzyl-1,4-dioxo-4-
Morpholino] butyl-3- (4-thiazolyl) -DL-alanyl-statyl-L-leucyl-N ^α -benzyloxycarbonyl-L-lysineamide N- [2 (R) -benzyl-1 synthesized in Example 3b) ,Four
0.31 g (0.7 mmol) of -dioxo-4-morpholino] butyl-3- (4-thiazolyl) -DL-alanine hydrazide was dissolved in 8 ml of dimethylformamide, cooled to -60 ° C and 0.60 ml of 4N hydrochloric acid / dioxane solution. After adding 0.11 ml of isoamyl nitrite, the mixture was stirred at -20 ° C for 10 minutes. The reaction solution was cooled to −60 ° C. again, and N-methylmorpholine 0.30
ml (2.7 mmol) was added to neutralize. Example 2
N-t-butoxycarbonyl-statyl-L-leucyl-N ^α -benzyloxycarbonyl-L synthesized in c)
-Lysine amide 0.59 g (0.87 mmol) of t-butoxycarbonyl group was removed using 4N hydrochloric acid / dioxane to obtain statyl-L-leucyl-N ^α -benzyloxycarbonyl-L-lysine amide hydrochloride dimethyl ester. Formamide solution 5 ml and N-methylmorpholine 0.10 ml
(0.91 mmol) was added and the mixture was stirred at 4 ° C overnight. A double amount of ethyl acetate was added to the reaction solution, washed with 1N sulfuric acid, 5% aqueous sodium hydrogen carbonate solution and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with a silica gel thin layer plate (developing solvent: chloroform / methanol = 10/1), and N- [2
(R) -benzyl-1,4-dioxo-4-morpholino]
Butyl-3- (4-thiazolyl) -DL-alanyl-statyl-L-leucyl-N ^α -benzyloxycarbonyl-L-lysine amide trihydrate 250 mg (37%) was obtained.

Melting point 98-100 ° C Elemental analysis: C ₄₉ H ₇₀ N ₈ O ₁₀・ 3H ₂ O Calculated: C, 57.85; H, 7.53; N, 11.02; S, 3.15 Found: C, 57.94; H, 7.41 ; N, 10.81; S, 3.06 d) N- [2 (R) -benzyl-1,4-dioxo-4-
Morpholino] butyl-3- (4-thiazolyl) -DL-alanyl-statyl-L-leucyl-ε-L-lysineamide dihydrofluoride 140 mg (0.14 mmol) of the compound obtained in example 3c)
Was treated with anisole and hydrofluoric acid for 30 minutes, concentrated under reduced pressure, washed with n-hexane and then crystallized by adding diethyl coatel to obtain 90 mg (75%) of the title compound.

Melting point 156-159 [deg.] C. Example 4. N- [2 (R) -benzyl-1,4-dioxo-4-morpholino] butyl-3- (4-thiazolyl) -DL-alanyl-statyl-L-isoleucyl- [epsilon]. -L-lysine amide dihydrofluoride salt N- [2 (R) -benzyl-1,4 synthesized in Example 3b)
-Dioxo-4-morpholino] butyl-3- (4-thiazolyl) -DL-alanine hydrazide and t-butoxycarbonyl-L-isoleucine in place of t-butoxycarbonyl-L-leucine as in Example 2c). N-t-butoxycarbonyl-statyl-L synthesized in
-Isoloyl-N ^α -benzyloxycarbonyl-L-
Reaction and treatment with lysine amide as in Example 3c) gave N- [2 (R) -benzyl-1,4-dioxo-4-morpholino] butyl-3- (4-thiazolyl) -DL- Alanyl-statyl-L-isoleucyl-N ^α -benzyloxycarbonyl-L-lysine amide monohydrate (melting point 184
~ 187 ° C) was obtained and reacted and treated in the same manner as in Example 3d) to obtain the target compound.

Melting point 137-142 ° C Reference example 1. (1-Naphtyl) methyl- (3-pyridyl) methylmalonic acid diethyl ester 0.69 g (30 mmol) of sodium metal was added to absolute ethanol 2
After dissolving in 0 ml, ethanol was concentrated to dryness. This was dissolved in 20 ml of dimethylformamide, and 9.0 g (30 mmol) of diethyl (1-naphthylmethyl) malonate was added to 10 ml under ice cooling.
The solution dissolved in dimethylformamide of was added dropwise, stirred for 10 minutes, and further stirred at room temperature for 1 hour. On the other hand, a solution prepared by dissolving 0.69 g of metallic sodium in 20 ml of absolute ethanol was cooled, and 4.92 g of 30-picolyl chloride hydrochloride (30
Was added, and the mixture was stirred for 30 minutes and then concentrated under reduced pressure to dryness.
This was dissolved in 20 ml of dimethylformamide, the reaction solution obtained above was added, and the mixture was stirred under ice cooling for 1 hour and then at 50 ° C to 60 ° C for 8 hours. Then, dimethylformamide was distilled off under reduced pressure, 100 ml of water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 3/1). Collect the target eluate and concentrate under reduced pressure to give an oil 5.9g
(50.2%) was obtained.

Elemental analysis C ₁₉ H ₁₇ NO ₂ Calculated: C, 78.33; H, 5.88 ; N, 4.81 Found: C, 78.33; H, 6.02 ; N, 4.72 Reference Example 2. 2 (RS) - (1- Naphthyl) methyl-3- (3-pyridyl) propionic acid Diethyl (1-naphthyl) methyl-3- (3-pyridyl) methylmalonate 5.9 g (15 mmol) of 85% potassium hydroxide 5.9 g (98 mmol) water 40 ml and n-butanol
The mixture was added to 40 ml of a mixed solution and refluxed for 7 hours. Butanol was concentrated under reduced pressure, the residue was acidified with concentrated acid salt, and then adjusted to pH 6 to 7 with 2N sodium hydroxide. The deposited precipitate was removed and purified by silica gel column chromatography (developing solvent: CHCl ₃ / methanol = 9: 1). The desired eluate was collected and concentrated under reduced pressure to obtain 2.04 g (46.7%) of the desired product.

Mp one hundred fifty-seven to one hundred fifty-eight ° C. Elemental analysis C ₂₄ H ₂₅ NO ₄ Calculated: C, 73.64; H, 6.44 ; N, 3.58 Found: C, 73.65; H, 6.46 ; N, 3.57 Reference Example 3. N-3 -Phenylpropionyl- (S)-(-)-4-
Benzyl-2-oxazolidinone (S)-(-)-4 in 200 ml of anhydrous tetrahydrofuran
12.41 g (70 mmol) of -benzyl-2-oxazolidinone was dissolved, and a n-butyllithium-hexane solution (77 mmol) was added dropwise at -78 ° C under a nitrogen atmosphere. After stirring for 30 minutes, 13.0 g of 3-phenylpropionyl chloride (77
A solution of 100 millimoles) dissolved in 100 ml of anhydrous tetrahydrofuran was slowly added dropwise at the same temperature and stirred for 1 hour. After 1 hour, saturated saline was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / n-hexane = 1/4) and recrystallized (ethyl acetate- Hexane) was performed to give 16.9 g (78%) of the title compound as white crystals.

Melting point 92-95 ° C Elemental analysis value Calculated as C ₁₉ H ₁₉ NO ₃ Calculated value: C, 73.77; H, 6.19; N, 4.53 Measured value: C, 73.57; H, 6.28; N, 4.41 Mass spectrum, m / e: 309 (M ⁺ ) Reference Example 4. (2R) -N- (3-carbobenzoxy-2-benzyl-
1-oxo-propyl]-(S)-(-)-4-benzyl-2-oxazolidinone 50 ml anhydrous tetrahydrofuran at -78 ° C under a nitrogen atmosphere, 2.91 ml diisopropylamine (20.8 mmol) and n-butyl lithium. Add 13.40 ml of hexane solution and add 3
Stir for 0 minutes. In this solution, obtained in Reference Example 3,
N- (3-phenylpropionyl)-(S)-(-)-
A solution of 5.35 g (17.3 mmol) of 4-benzyl-2-oxazolidinone in 20 ml of anhydrous tetrahydrofuran was added, and the mixture was further stirred for 1 hour at the same temperature. After the reaction,
A solution prepared by dissolving 5.74 ml (36.2 mmol) of bromoacetic acid benzyl ester in 10 ml of anhydrous tetrahydrofuran was added dropwise, and the mixture was further stirred for 3 hours. After completion of the reaction, saturated saline was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/5) to give the title compound as a colorless oily substance. As a result, 5.47 g (69%) was obtained.

Reference Example 5. (2R) -N- [2-benzyl-1,4-dioxo-4-morpholinobutyl]-(S)-(-)-4-benzyl-2
-Oxazolidinone 5.10 g (11.1 mmol) of the compound obtained in Reference Example 4 was dissolved in 100 ml of ethanol to give 10% palladium-carbon (500 mg).
Was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. After completion of the reaction, the catalyst was removed and the liquid was concentrated under reduced pressure. The residue was dissolved in 50 ml of anhydrous tetrahydrofuran, and under a nitrogen atmosphere under ice-cooling, 1.16 ml (13.3 mmol) of morpholine, 2.02 ml (13.3 mmol) of dimethyl cyanophosphate and 1.86 ml (13.3 mmol) of triethylamine were sequentially added, and 2 more were added. Stir for hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was
Medium pressure silica gel column chromatography (developing solvent:
Purification with ethyl acetate / n-hexane = 1/1) gave the title compound as white crystals, 3.90 g (80%).

Melting point 56-59 ° C Elemental analysis: Calculated as C ₂₅ H ₂₈ N ₂ O ₅ : C, 68.79; H, 6.47; N, 6.42 Found: C, 68.59; H, 6.75; N, 6.50 Mass spectrum, m / e: 436 (M ⁺ ) Reference Example 6. (2R) -2-benzyl-4-morpholino-4-oxo-
Butanoic acid 3.70 g (8.5 mmol) of the compound obtained in Reference Example 5 was dissolved in 80 ml of tetrahydrofuran and 30 ml of water, and under ice-cooling, 711 mg (16.9 mmol) of lithium hydroxide monohydrate was added to the same temperature. And stirred for 3 hours. After completion of the reaction, tetrahydrofuran was distilled off under reduced pressure, 10% aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with methylene chloride. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid under ice cooling and extracted with methylene chloride. did.
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1.75 g (75%) of the title compound as a white oily substance.

Mass spectrum, m / e: 277 (M ⁺ )

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location C07C 275/04 279/08 279/14 309/15 317/50 7419-4H 323/52 323/59 7419-4H 323/60 7419-4H 323/63 7419-4H C07K 5/06 8318-4H (72) Inventor Yasuki Iijima 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Invention Eitaka Takahagi 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Tatsuro Kofu Shigenobu, Ehime Prefecture 2301-7 Takuro, Municipal Takubo Hiwada Kunio Hiwada Shigenobu, Ehime Prefecture Machida Kubo 2108-6

Claims (1)

[Claims] 1. And a pharmacologically acceptable salt thereof. In the above formula, R ¹ is a group of the formula —B—R ⁷ (wherein B represents a linear or branched lower alkylene group, and R ⁷ represents an aryl group, a heteroaryl group or a heterocyclylcarbonyl group). Show.)
Or a group of the formula —E—R ⁸ (wherein E represents a lower alkylene group which may be interrupted by one oxygen atom, R ⁸ represents a lower alkoxy group, an aryloxy group, an arylthio group, an aralkyloxy group or Represents a heterocyclyl group), R ² represents an aryl group or a heteroaryl group, R represents a hydrogen atom or a lower alkyl group, R ³ represents a hydrogen atom, or an optionally substituted C _1-. C ₁₀ alkyl group (the number of the substituents may be one or two, and they may be a halogen atom, a trifluoromethyl group, a trichloromethyl group, a hydroxyl group, a lower alkoxy group, an aryloxy group, an aralkyloxy group, a lower aliphatic acyloxy group. Group, mercapto group,
Lower alkylthio group optionally substituted with lower aliphatic acylamino, arylthio group, aralkylthio group, lower alkylsulfinyl group, arylsulfinyl group, lower alkylsulfonyl group, arylsulfonyl group, amino group, mono- or di- Lower alkylamino group, arylamino group, lower aliphatic acylamino group, arylacylamino group, lower alkoxycarbonylamino group, aralkyloxycarbonylamino group, carboxy group, lower alkoxycarbonyl group, aryloxycarbonyl group,
Aralkyloxycarbonyl group, carbamoyl group, mono- or di - lower alkylcarbamoyl group, a ureido group, thioureido group, Kuanijiru group, C ₃ -C ₇ cycloalkyl group, C ₅ -C ₈ cycloalkenyl group, an aryl group or a heteroaryl Show. ), C ₃ -C ₅ alkenyl group, C ₃ -C ₅
Alkynyl group, C ₃ -C ₇ cycloalkyl group, C ₅ -C ₈ cycloalkenyl group, an aryl group or a heteroaryl group, R ⁴ represents an isopropyl group, a cycloalkyl group or a phenyl group of C ₃ -C ₇ , R ⁵ represents a linear or branched C ₁ -C ₅ alkyl group, and R ⁶ is a substituted C _1-, which may be interrupted by a nitrogen atom.
C ₁₀ alkyl group [wherein the substituents may be 1, 2 or 3 and these are amino group, 6-membered cyclic heterocyclyl lower alkylamino group, hydroxy lower alkylamino group, guanidyl group, substituted phenyl Group (cyclic substituent is amino in addition to amino lower alkyl group or hydroxyl group,
A lower alkoxy group having mono-lower alkylamino, di-lower alkylamino, heterocyclyl or heterocyclyl lower alkylamino as a substituent is shown. ), A sulfo group, a hydroxyl group, a carboxy group, a lower alkoxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylcarbamoyl group, or a pyridyl group. ] Is shown. However, the C ₁ -C ₁₀ alkyl group of R ⁶ is an amino group, a 6-membered cyclic heterocyclyl lower alkylamino group, a hydroxy lower alkylamino group, a guanidyl group, a substituted phenyl group or a substituted group of a sulfo group. Be sure to have one or more selected substitutions.